Arsenic trioxide (As302,) has been shown in clinical trials to have a major therapeutic effect in the acute myeloid leukemia (AML) subtype called acute promyeloctyic leukemia (APL). Preliminary in vitro results have suggested that As302 has antineoplastic activity in other tumors including non-APL AML, lymphoid and myeloma cell lines by several mechanisms that overcome cell resistance to chemotherapy. One mechanism is by As3O2 induced apoptosis via intracellular glutathione (GSH) and increased production of reactive oxygen species (ROS). Cancer cells (including AML) with lower glutathione (GSH) levels are more sensitive to As203 induced apoptosis and compounds that decrease intracellular GSH can induce or increase this effect of As203. Several studies have shown that Vitamin C/ascorbic acid (AA) can enhance As302 induced apoptosis in non-AML APL AML, and multiple myeloma cell lines, suggesting that combining As302 with AA may be an effective antineoplastic approach in tumors refractory to chemotherapy. From pilot clinical studies performed so far, this combination could also be less toxic than intensive chemotherapy. Thus, As302 plus AA could also be a safer alternative or possible complementary approach to treat non-APL AML patients who do not want or cannot be treated with intensive conventional chemotherapy. In vitro studies with As302 AA have been done on very few non-APL AML cell lines but samples freshly obtained from many patients. Thus, no patient-to-patient variability is known. We therefore propose to study antineoplastic activity in vitro of As302 by inducing apoptosis and test if such activity could be enhanced by AA on non-APL AML cells freshly obtained from patients. We will also study the mechanism of action focusing on GSH depletion and ROS production. Since phase I studies of combination of As302 plus ascorbic acid have already been found to be safe and well tolerated we will conduct a pilot phase II clinical trial to determine the feasibility, safety and possible efficacy of the combination in patients with non-APL AML who had failed or will not receive chemotherapy. In summary, this combination may have higher benefit/risk ratio in non-APL AML patients resulting in an overall better outcome with less toxicity than conventional chemotherapy.